TY - JOUR
T1 - Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons
AU - Bolze, Alexandre
AU - Boisson, Bertrand
AU - Bosch, Barbara
AU - Antipenko, Alexander
AU - Bouaziz, Matthieu
AU - Sackstein, Paul
AU - Chaker-Margot, Malik
AU - Barlogis, Vincent
AU - Briggs, Tracy
AU - Colino, Elena
AU - Elmore, Aurora C.
AU - Fischer, Alain
AU - Genel, Ferah
AU - Hewlett, Angela
AU - Jedidi, Maher
AU - Kelecic, Jadranka
AU - Krüger, Renate
AU - Ku, Cheng Lung
AU - Kumararatne, Dinakantha
AU - Lefevre-Utile, Alain
AU - Loughlin, Sam
AU - Mahlaoui, Nizar
AU - Markus, Susanne
AU - Garcia, Juan Miguel
AU - Nizon, Mathilde
AU - Oleastro, Matias
AU - Pac, Malgorzata
AU - Picard, Capucine
AU - Pollard, Andrew J.
AU - Rodriguez-Gallego, Carlos
AU - Thomas, Caroline
AU - Bernuth, Horst Von
AU - Worth, Austen
AU - Meyts, Isabelle
AU - Risolino, Maurizio
AU - Selleri, Licia
AU - Puel, Anne
AU - Klinge, Sebastian
AU - Abel, Laurent
AU - Casanova, Jean Laurent
N1 - Publisher Copyright:
© 2018 National Academy of Sciences. All Rights Reserved.
PY - 2018/8/21
Y1 - 2018/8/21
N2 - Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA, encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here 11 new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 5′-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that 6 of 18 (33%) protein-coding mutations and the two (100%) 5′-UTR mutations display incomplete penetrance. Three mutations were identified in two independent kindreds, due to a hotspot or a founder effect. Finally, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.
AB - Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA, encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here 11 new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 5′-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that 6 of 18 (33%) protein-coding mutations and the two (100%) 5′-UTR mutations display incomplete penetrance. Three mutations were identified in two independent kindreds, due to a hotspot or a founder effect. Finally, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.
KW - Incomplete penetrance
KW - Isolated congenital asplenia
KW - RPSA
KW - Ribosomopathy
KW - Spleen
UR - http://www.scopus.com/inward/record.url?scp=85051824997&partnerID=8YFLogxK
U2 - 10.1073/pnas.1805437115
DO - 10.1073/pnas.1805437115
M3 - 文章
C2 - 30072435
AN - SCOPUS:85051824997
SN - 0027-8424
VL - 115
SP - E8007-E8016
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 34
ER -